WO2004106325A1 - Promedicaments de 1-(1-hydroxy-5-isoquinolinesulfonyl)homopiperazine - Google Patents
Promedicaments de 1-(1-hydroxy-5-isoquinolinesulfonyl)homopiperazine Download PDFInfo
- Publication number
- WO2004106325A1 WO2004106325A1 PCT/US2004/016919 US2004016919W WO2004106325A1 WO 2004106325 A1 WO2004106325 A1 WO 2004106325A1 US 2004016919 W US2004016919 W US 2004016919W WO 2004106325 A1 WO2004106325 A1 WO 2004106325A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- groups
- sufonyl
- diazepin
- Prior art date
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- 0 *c1nccc2c1cccc2S(N1CCNCCC1)(=O)=O Chemical compound *c1nccc2c1cccc2S(N1CCNCCC1)(=O)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- U.S. Patent No. 4,678,783 discloses a class of substituted isoquinolinesulfonyl compounds that are useful in treating a variety of disorders including angina. Included in the disclosure of U.S. Patent No. 4,678,783 is the compound 1-(5-isoquinolinesuIfonyl) homopiperazine,
- the major active metabolite of fasudil is 1-(1-hydroxy-5-isoquinoIinesulfonyl) homopiperazine (or hydroxyfasudil)
- Hydroxyfasudil has a more specific inhibitory effect on Rho-kinase than fasudil (Shimokawa et al. (1999) Cardiovas. Res. 43:1138-1141 ).
- 1 is (a) alkyl, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, (aryl)alkyl, (heteroaryl)alkyl,
- R 2 is alkyl, cycloalkyl, alkenyl, alkynyl, (cycloalkyl)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (heterocyclo)alkyl, aryl, heteroaryl or heterocyclo any of which may be optionally independently substituted as valence allows with 1 to 3 Z groups; and Z at each occurrence is independently
- U 1 and U 2 are each independently
- V 1 , V a , V 2 , V 3 and V 4 (1 ) are each independently hydrogen or a group provided in the definition of Z ; or
- V 2 and V 3 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of Z, or (3) V 2 or V 3 , together with V 1 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of Z; and U 3 and U 4 are each independently (1 ) a single bond,
- the present invention is further directed to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I) together with a pharmaceutically acceptable vehicle or carrier.
- the present invention is further directed to a method of treating a disorder mediated by rho kinase comprising administering to a patient in need thereof an amount of a compound of Formula (I) sufficient to provide in vivo a therapeutically effective amount of hydroxyfasudil.
- the prodrug compounds of Formula (I) may have less potential for in vivo drug-drug interaction as they may not interact with critical cytochrome P450 isoenzymes involved in the metabolism of drugs.
- Preferred compounds of Formula I include compounds where R 1 is alkyl, cycloalkyl, (cylcoalkyl)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl.
- More preferred compounds of Formula I include compounds where R is alkyl.
- Most preferred compounds of Formula I include compounds where R 1 is C-t - C 3 alkyl.
- alkyl is used herein at all occurrences (as a group per se or a part of a group) to mean straight or branched chain alkyl groups of 1 to 6 carbon atoms, unless the chain length is otherwise indicated, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
- Alkyl groups may also be substituted one or more times by halogen, aryl, substituted aryl, hydroxy, methoxy, amino, substituted amino, nitro, carboxy, or cyano.
- alkylene groups e.g., methylene
- alkenylene groups alkynylene groups
- cycloalkyl refers to saturated and partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 7 carbons, forming the ring.
- the rings of multi-ring cycloalkyls may be either fused, bridged and/or joined through one or more spiro union to 1 or 2 aromatic, cycloalkyl or heterocyclo rings.
- Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyciododecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl,
- Alkoxy means alkyl-O- groups in hich the alkyl portion (substituted or unsubstituted) is in accordance with the previous definition. Suitable alkoxy groups include methoxy, ethoxy, propoxy and butoxy.
- Alkenyl represents C 2 -C 6 carbon chains having one or two unsaturated bonds, provided that two unsaturated bonds are not adjacent to each other.
- halo or halogen are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine or bromine.
- Halogenated is analogous and refers to a degree of halogen substitutions from single to full (per) substitution.
- haloalkyl represents a straight or branched alkyl chain substituted by 1 to 5 halo atoms, which can be attached to the same or different carbon atoms, e.g., -CH 2 F, -CHF 2 , -CF 3 , F 3 CCH 2 - and -CF 2 CF 3 .
- heteroaryl refers to monocyclic and bicyclic aromatic rings containing from 5 to 10 atoms, which includes 1 to 4 hetero atoms such as nitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl or heterocyclo ring, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
- heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazoiyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrol
- heterocyclic or “heterocyclo” as used herein by itself or as part of another group refer to optionally substituted, fully saturated or partially unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, preferably containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring.
- Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
- the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valance allows.
- the rings of multi-ring heterocycles may be either fused, bridged and/or joined through one or more spiro unions to 1 or 2 aromatic, heteroaryl or cycloalkyl rings.
- heterocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl , oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyI, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1 ,3-dioxolane and tetrahydro-1 ,1-dioxothienyl,
- aromatic homocyclic i.e., hydrocarbon
- biphenyl i.e., naphthyl (including l-naphthyl and 2- naphthyl) and antracenyl)
- aromatic homocyclic i.e., hydrocarbon
- biphenyl i.e., biphenyl
- naphthyl including l-naphthyl and 2- naphthyl
- antracenyl such as phenyl, biphenyl, naphthyl (including l-naphthyl and 2- naphthyl) and antracenyl) and may optionally include one to three additional rings (either cycloalkyl, heterocyclo or heteroaryl) fused thereto. Examples include:
- arylalkyl refers to a residue in which an aryl moiety is attached to the parent structure via an alkyl residue, wherein the aryl and alkyl portions are in accordance with the descriptions above.
- terms such as “(heteroaryl)alkyF', “(heterocyclo)alkyl”, and “(cycloalkyl)alkyP' refer respectively to heteroaryl, heterocyclo and cycloalkyl moeities that are attached to the parent structure via an alkyl residue.
- “Solvates” of the compounds of formula I are preferably hydrates.
- “Pharmaceutically acceptable salt” includes both acid and base addition salts.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
- “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethyIaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
- Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
- prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to hydroxyfasudil.
- prodrug refers to a metabolic precursor of hydroxyfasudil that is pharmaceutically acceptable.
- a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
- Prodrugs are typically rapidly transformed in vivo to yield hydroxyfasudil, for example, by hydrolysis in blood.
- the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
- the compounds of the invention are prodrugs of fasudil's major active metabolite, hydroxyfasudil, and thus are useful in treating disorders mediated by rho kinase.
- disorders include hypertension (e.g., systolic hypertension, pulmonary hypertension, essential hypertension, renal hypertension and the like), coronary vasopasm (angina), atherosclerosis, scleroderma, Barter syndrome, transplant atherosclerosis, restenosis, stent stenosis, vein graft stenosis, Reynauds, hypertrophic cardiomyopathy, myocardial infarction, thrombosis, congestive heart failure, aneurysm, cardiac hypertrophy, stroke, cerebral vasopasm (subarachnoid hemorrhage), migraine, spinal cord regeneration, neuronal regeneration, cerebrovascular contraction, cerebrovascular thrombosis, asthma, peripheral circulatory disorders (including, ischemia and intermittent claudication
- Administration of a compound of the invention, as a single stereoisomers, a mixture of stereoisomers, or as a racemic mixture of stereoisomers, or as a pharmaceutically acceptable salt thereof, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
- administration can be, for example, orally, nasally, parenterally, pulmonary, topically, transdermally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, aerosols, patches, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
- compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
- compounds of the present invention may be administered in an amount from 20 to 300 mg per day for an adult in 2 to 3 administrations, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers, or as a pharmaceutically acceptable salt thereof.
- the results of recent clinical trials with fasudil suggest that the most preferred dose to effectively treat angina is one that results in plasma concentrations of hydroxyfasudil between about 200 ng/mL to about 1500 ng/mL.
- the compounds of the invention are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disease-states; and the host undergoing therapy.
- a pharmaceutically acceptable composition containing a compound(s) of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers, or as a pharmaceutically acceptable salt thereof is formed by the incorporation of one or more of the normally employed pharmaceutically acceptable excipient(s), such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharine, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like.
- Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations (such as those described in U.S. Patent 6,699,508) and the like.
- compositions will take the form of capsule, caplet or tablet and therefore will also contain a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as croscarmellose sodium or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.
- a diluent such as lactose, sucrose, dicalcium phosphate, and the like
- a disintegrant such as croscarmellose sodium or derivatives thereof
- a lubricant such as magnesium stearate and the like
- a binder such as a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.
- the compounds of the invention, or their pharmaceutically acceptable salts may also be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient disposed in a carrier that slowly dissolves within the body, e.g., polyoxyethylene glycols and polyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).
- a carrier that slowly dissolves within the body
- PEG polyoxyethylene glycols and polyethylene glycols
- Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., a compound(s) of the invention as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers, or as a pharmaceutically acceptable salt thereof, and optional pharmaceutical acceptable adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
- a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
- a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
- auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
- composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; or as a cyclodextrin clathrate thereof, or as a pharmaceutically acceptable salt thereof, for treatment of a disease-state characterized by inflammation in accordance with the teachings of this invention.
- the compounds of the present invention may be employed alone or in combination with other suitable therapeutic agents, such as diruetics, anti-hypertensive agents, beta blockers, calcium channel blockers, nitrates, and phosphodiesterase inhibitors (including both cGMP and cAMP). If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described and the other pharmaceutically active agent within its effective dosage range.
- suitable therapeutic agents such as diruetics, anti-hypertensive agents, beta blockers, calcium channel blockers, nitrates, and phosphodiesterase inhibitors (including both cGMP and cAMP).
- PDR Physicians' Desk Reference
- Ether compounds of Formula I can be made according to the following general procedure:
- Ester compounds of Formula I can be made according to the following general procedure:
Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US47414103P | 2003-05-29 | 2003-05-29 | |
US60/474,141 | 2003-05-29 |
Publications (1)
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WO2004106325A1 true WO2004106325A1 (fr) | 2004-12-09 |
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ID=33490698
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2004/016918 WO2004105757A2 (fr) | 2003-05-29 | 2004-05-28 | Utilisation des inhibiteurs de la rho kinase dans le traitement de l'anevrisme et de l'hypertrophie cardiaque |
PCT/US2004/016919 WO2004106325A1 (fr) | 2003-05-29 | 2004-05-28 | Promedicaments de 1-(1-hydroxy-5-isoquinolinesulfonyl)homopiperazine |
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PCT/US2004/016918 WO2004105757A2 (fr) | 2003-05-29 | 2004-05-28 | Utilisation des inhibiteurs de la rho kinase dans le traitement de l'anevrisme et de l'hypertrophie cardiaque |
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US (2) | US20050014783A1 (fr) |
WO (2) | WO2004105757A2 (fr) |
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WO2008077555A2 (fr) | 2006-12-27 | 2008-07-03 | Sanofi-Aventis | Nouveaux dérivés d'isoquinoline et d'isoquinolinone substitués |
EP2285217A1 (fr) * | 2008-05-12 | 2011-02-23 | Amnestix, Inc. | Composés utilisables pour l'amélioration de l'apprentissage et de la mémoire |
EP2385047A1 (fr) | 2005-07-26 | 2011-11-09 | Sanofi | Dérivés dýisoquinoléine à substitution pipéridinyle |
US8278294B2 (en) | 2006-12-27 | 2012-10-02 | Sanofi | Substituted isoquinoline and isoquinolinone derivatives as inhibitors of Rho-kinase |
US8399482B2 (en) | 2008-06-24 | 2013-03-19 | Sanofi | 6-substituted isoquinolines and isoquinolinones |
WO2013057592A3 (fr) * | 2011-09-14 | 2013-06-13 | King Abdullah University Of Science And Technology | Traitement de la drépanocytose |
US8501736B2 (en) | 2005-06-28 | 2013-08-06 | Sanofi | Isoquinoline derivatives |
US8524737B2 (en) | 2008-06-24 | 2013-09-03 | Sanofi | Bi- and polycyclic substituted isoquinoline and isoquinolinone derivatives |
US8541449B2 (en) | 2008-06-24 | 2013-09-24 | Sanofi | Substituted isoquinolines and isoquinolinones as Rho kinase inhibitors |
US8609691B2 (en) | 2005-07-26 | 2013-12-17 | Sanofi | Cyclohexylamin isoquinolone derivatives |
US8710228B2 (en) | 2006-12-27 | 2014-04-29 | Sanofi | Cycloalkylamine substituted isoquinoline derivatives |
US8710077B2 (en) | 2006-12-27 | 2014-04-29 | Sanofi | Cycloalkylamine substituted isoquinoline and isoquinolinone derivatives |
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US20140378441A1 (en) * | 2013-04-24 | 2014-12-25 | Kyushu University, National University Corporation | Therapeutic agent for ocular fundus disease |
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WO2020087901A1 (fr) * | 2018-10-30 | 2020-05-07 | 北京盈科瑞创新药物研究有限公司 | Inhibteur de rho kinase, son procédé de préparation et son utilisation |
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WO2020177291A1 (fr) * | 2019-03-04 | 2020-09-10 | 中国药科大学 | Sel de composé de fasudil, son procédé de préparation et son utilisation |
WO2020253882A1 (fr) * | 2019-06-21 | 2020-12-24 | 中山大学中山眼科中心 | Dérivés d'isoquinolinone servant d'inhibiteurs de protéine kinase rock et leur utilisation |
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ATE546143T1 (de) * | 2002-08-29 | 2012-03-15 | Santen Pharmaceutical Co Ltd | Mittel zur behandlung von glaukom mit einem rho- kinase-hemmer und prostaglandinen |
KR101223886B1 (ko) * | 2002-11-18 | 2013-01-17 | 산텐 세이야꾸 가부시키가이샤 | Rho 키나아제 억제제와 β 차단약으로 이루어진 녹내장 치료제 |
US20050283841A1 (en) * | 2004-02-02 | 2005-12-22 | Mckinsey Timothy A | Inhibition of protein kinase C-related kinase (PRK) as a treatment for cardiac hypertrophy and heart failure |
ES2411965T3 (es) | 2004-04-02 | 2013-07-09 | The Regents Of The University Of California | Métodos y composiciones para tratar y prevenir enfermedad asociada con integrina alfa V beta 5 |
CR9465A (es) | 2005-03-25 | 2008-06-19 | Surface Logix Inc | Compuestos mejorados farmacocineticamente |
CA2659289A1 (fr) * | 2006-08-10 | 2008-02-14 | Translational Genomics Research Institute | Composes pour ameliorer l'apprentissage et la memoire |
EP2234487A4 (fr) * | 2007-12-19 | 2011-09-07 | Scripps Research Inst | Anilides et analogues utilisés comme inhibiteurs de la rho kinase |
EP2317849A4 (fr) * | 2008-06-26 | 2011-11-02 | Inspire Pharmaceuticals Inc | Procédé permettant de traiter des maladies pulmonaires par des composés inhibiteurs de rho kinase |
WO2015165341A1 (fr) | 2014-04-28 | 2015-11-05 | 南京明德新药研发股份有限公司 | Dérivé d'isoquinolinesulfonyle utilisé comme inhibiteur de la rho kinase |
US10857157B2 (en) | 2015-01-26 | 2020-12-08 | BioAxone BioSciences, Inc. | Treatment of cerebral cavernous malformations and cerebral aneurysms with rho kinase inhibitors |
WO2018118109A1 (fr) * | 2016-12-21 | 2018-06-28 | BioAxone BioSciences, Inc. | Inhibiteur ba-1049 (r) de rho kinase et ses métabolites actifs |
CN113227054A (zh) | 2018-11-06 | 2021-08-06 | 切尔韦洛治疗有限责任公司 | Rock激酶抑制剂 |
US11248004B2 (en) | 2018-11-06 | 2022-02-15 | Cervello Therapeutics, Llc. | Substituted isoquinolines as rock kinase inhibitors |
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- 2004-05-28 US US10/857,572 patent/US20040266755A1/en not_active Abandoned
- 2004-05-28 WO PCT/US2004/016918 patent/WO2004105757A2/fr active Application Filing
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Also Published As
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US20050014783A1 (en) | 2005-01-20 |
US20040266755A1 (en) | 2004-12-30 |
WO2004105757A3 (fr) | 2005-05-12 |
WO2004105757A2 (fr) | 2004-12-09 |
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